title: Through the open door: Preferential binding of dasatinib to the active form of BCR-ABL unveiled by in silico experiments.
abstract: Dasatinib is a second-generation BCR-ABL inhibitor approved for the treatment of patients with chronic myeloid leukemia, both in the frontline and in the imatinib-resistant/intolerant settings. The high affinity of dasatinib for the protein is currently assumed to result from its ability to bind both the active and inactive conformations of the BCR-ABL kinase. In the present work, using state of the art molecular simulation techniques we prove that dasatinib exhibits a highly selective preference for the active (open) BCR-ABL conformation. By using three different BCR-ABL conformations (active, inactive, and intermediate inactive) we show that, from a thermodynamic standpoint, the affinity of dasatinib for BCR-ABL drastically decreases in the order: active > alternative inactive > inactive, as a result of differential contributions from the single residues lining the kinase binding pocket and the concomitant stabilization/destabilization of the kinase hydrophobic spine. Molecule-pulling experiments also corroborate this trend as significantly lower forces and smaller times are required to extract dasatinib from its inactive BCR-ABL complexes with respect to the active complex counterparts. Importantly, our results support recent NMR solution results demonstrating no evidence of dasatinib bound to the inactive form of BCR-ABL.
authors.affiliation: Molecular Simulations Engineering (MOSE) Laboratory - DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.forename: Paola
authors.initials: P
authors.lastname: Posocco
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
mesh_terms: D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib
keywords: BCR-ABL; Binding mode; Dasatinib; Hydrophobic-spine; Resistance